Approximately half of the cases of hydroxysteroid (17β) dehydrogenase X (HSD10) deficiency are due to a missense C>T mutation in exon 4 of the HSD17B10 gene. The resulting HSD10 (p.R130C) loses most or all catalytic functions, and the males with this mutation have a much more severe clinical phenotype than those carrying p.V65A, p.L122V, or p.E249Q mutations. We found that the mutated cytosine which is +2259 nucleotide from the ATG of the gene, is >90% methylated in both the active and inactive X chromosomes in two normal females as well as in the X chromosome of a normal male. Since 5-methylcytosine is prone to conversion to thymine by deamination, the methylation of this cytosine in normal X chromosomes provides an explanation for the prevalence of the p.R130C mutation among patients with HSD10 deficiency. The substitution of arginine for cysteine eliminates several hydrogen bonds and reduces the van der Waals interaction between HSD10 subunits. The resulting disruption of protein structure impairs some if not all of the catalytic and non-enzymatic functions of HSD10. A meta-analysis of residual HSD10 activity in eight patients with the p.R130C mutation showed an average 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) activity of only 6 (±5) % of the normal control level. This is significantly lower than in cells of patients with other, clinically milder mutations and suggests that the loss of HSD10/MHBD activity is a marker for the disorder.
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